PROJECT SUMMARY/ABSTRACT In New England?s rural northern states, the epidemic of opioid use disorder (OUD) and its related sequelae ? overdose, HIV, hepatitis C virus (HCV), sexually transmitted infections (STIs) and other infectious comorbidities ? present the most substantial challenges to public health and health care in decades. This two- stage, mixed-methods study will examine the epidemiology of IDU, its infectious consequences, and service accessibility among young persons who inject drugs (PWID) (UG3 phase) in 15 rural counties in Maine, New Hampshire and Vermont, and then implement an integrated telemedicine approach to treat OUD and reduce HIV, HCV, STIs, major bacterial infections (e.g. infective endocarditis, septic arthritis, osteomyelitis, epidural abscess) and overdose (UH3 phase). The UG3 phase will employ qualitative, quantitative, social network, geospatial, and laboratory methods to characterize the risk environment and epidemiology of OUD, its infectious complications, opioid overdose, risk behaviors, service use and needs in a respondent-driven sample (n=360) of young PWID in these rural counties. An environmental assessment of policy and infrastructure will examine available services, needs and gaps. This phase will also build capacity to collect and deliver specimens for centralized HCV transmission investigation and molecular epidemiologic analysis. In the UH3 phase, a Hybrid Type 1 implementation study will evaluate the effectiveness of a regionalized, integrated model of expanded service delivery for rural PWID. Using a stepped wedge design, the UH3 study will roll-out expanded services into primary care clinics and practices (PCCP) in these 15 rural northern New England counties using regional real-time tele-consultation, assessment and triage for HIV, hepatitis and OUD; and virtual, expert-facilitated bi-weekly case conferences around key topics (e.g., overdose prevention and HIV pre-exposure prophylaxis [PrEP]). PWID recruited during the UG3 phase in intervention counties will be recontacted and referred to these PCCP sites. Primary outcomes will be the proportion of PWID: (1) with an initial assessment at a PCCP site (intake); (2) with an initial visit who initiated any treatment service within 30 days (initiation?); (3) who initiated then received 3 more services within 180 days of initiation (engagement?); and (4) discussed and followed via telemedicine (?retention?). Process evaluation will assess barriers, facilitators, implementation problems and necessary adaptations. Secondary outcomes include the proportion of PWID who receive: HAV/HBV vaccination and STI testing; naloxone rescue kits; and OUD, HIV and HCV treatment, including HIV suppression and sustained HCV response (SVR) among those who receive services. This project is uniquely responsive to RFA-DA-17-014 in that it will provide in-depth understanding of high- risk rural PWID, inform community response strategies, and implement a comprehensive, integrated approach to treat OUD, reduce overdose and infectious complications among PWID in the rural US.